Since obesity represents a major risk factor for insulin resistance in the development of NIDDM, over the past 10 years we have focused our efforts in searching for the possible causes of obesity in the Pima Indian population. We have identified 4 familial metabolic parameters predicting body weight gain; a) a low metabolic rate, b) a high respiratory quotient, c) insulin sensitivity and d) a low spontaneous physical activity. We are presently investigating the underlying mechanisms of the variability of these 4 metabolic parameters. Recent data suggests that Pima Indians, have not only low levels of physical activity in adulthood, but already at the age of 5. Presently, we are conducting prospective studies of the impact of the level of physical activity assessed by doubly-labeled water on subsequent weight change. We are also pursuing studies designed to better assess the role of sympathetic nervous activity in carbohydrate metabolism, temperature regulation, substrate oxidation, and cardiovascular responses in this population. Since a low fat oxidation is a risk factor for body weight gain, we have recently demonstrated that skeletal muscle lipoprotein lipase activity and muscle fiber types account for part of this interindividual variability in macronutrient partitioning. In our search for linkages of obesity phenotypes and sub-phenotypes to candidate genes we have recently found that the tumor necrosis factor ` gene on chromosome 6 is linked to body fatness. However, this linkage is not related to any variant in the 3 exons of the genes. We are performing more obesity linkage studies with candidate genes and homologous regions of rodent obesity genes. Recent studies of mitochondrial DNA have provided an association between a variant in the sub-unit 1 of the NADH dehydrogenase gene and resting metabolic rate. However, this variant is not associated with differences in in vitro mitochondrial respiration.